DESCRIPTION (from applicant's abstract) Female gender is a risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests that the massive reduction in estrogen levels that occurs in women following menopause appears to be the primary variable underlying this risk factor. Importantly, the clinical use of estrogen replacement therapy in postmenopausal women has been demonstrated to both delay the onset of AD and slow its progression. Because estrogen has many cellular effects potentially relevant to a protective role against AD, currently it is unclear what specific estrogen action(s) are salient to its inhibition of AD pathology. In this grant application, the applicants propose a novel neuroprotective mechanism of estrogen and predict that it functions to increase neuronal resilience against degenerative stimuli implicated in AD neurodegeneration. Based upon recent advances in the fields of endocrinology and oncology, they theorize that in estrogen responsive brain regions (e.g., hippocampus, entorhinal cortex, amygdala), estrogen activates its receptors, which initiates a genomic pathway that alters the expression of apoptosis- related proteins. In particular, their preliminary data suggest that estrogen significantly increases expression of the anti-apoptotic protein Bcl-XL. As a consequence of its regulation of apoptosis-related proteins, they theorize that estrogen sways the balance of neuronal apoptotic pathways toward enhanced viability, thereby increasing the resistance of estrogen-responsive neurons to apoptotic degeneration. Thus, the loss of estrogen following menopause is predicted to decrease levels of an important endogenous modulator of neuronal viability, rendering estrogen-responsive brain regions vulnerable to apoptotic challenge. The applicants propose three aims to investigate this novel theory: (1) Using cell culture and in vivo paradigms, they will evaluate estrogen's ability to regulate neuronal expresssion of apoptosis-related proteins. They will identify estrogen target proteins, determine the role of receptor activation and differential receptor subtype response, and examine possible synergism with other apoptosis modulators; (2) They will investigate predictions that functional consequences of estrogen's regulatory actions include decreased activation of specific apoptotic pathways (e.g., caspase-mediated proteolysis) and increased neuronal viability; (3) They will use quantitative image analysis techniques to correlate findings made in experimental systems (Aims 1 and 2) to the normal aged and AD brain. The applicants anticipate that their novel hypotheses will generate new insight into the ability of estrogen to modulate neuronal viability throughout life, from neural development through age-related neurodegenerative disorders.